4-Ethoxymethylphenol: A novel phytoestrogen that acts as an agonist for human estrogen receptors

Estrogen is the natural agonist of the estrogen receptor (ER). However, certain plant-derived compounds or phytoestrogens have been identified that mimic estrogens and act as agonists and/or antagonists of ERs, depending on subtype and target tissue. Using thin layer chromatography (TLC), gas chromatography-mass spectrometry (GC-MS), and proton nuclear magnetic resonance (¹H-NMR), we identified a simple phenol, 4-ethoxymethylphenol (4EM), found in Maclura pomifera that acts as an agonist of ER-α and ER-β in HeLa and MCF-7 cells. To study the effect of 4EM on ER-α and ER-β activity, we performed transient transfection assays and showed that 4EM activated ER-dependent gene transcription in a dose-dependent manner on both ER subtypes and this activity was inhibited by trans-4-hydroxytamoxifen (4HT). Further, 4EM-mediated transcription in ER-α, like estrogen, was enhanced in the presence of coactivators, steroid receptor coactivator-1 (SRC-1), CREB binding proteins (CBP), and E6-associated protein (E6-AP). We found that 4EM was specific for ER and did not activate transcription of the progesterone receptor.